Spinal cord stimulation (SCS) is a minimally invasive therapy used for the treatment of refractory neuropathic pain. It is believed that SCS mediates pain relief by electrical stimulation of A? fibers (A?-ES), however a detailed understanding of its biological basis is lacking, particularly concerning how it engages spinal cord nociceptive pathways. The long-term goals of this proposal are to delineate the spinal mechanisms of SCS-induced analgesia in an effort to optimize its clinical implementation for the treatment of chronic pain. The overall objective of the present application is to dissect the influence of A?-ES on defined neuronal microcircuits, and test the role of a critical candidate subpopulation for the analgesic effects of A?-ES. The central hypothesis is that A?-ES achieves analgesia by inducing dynamic changes in specific populations of spinal cord neurons residing in the superficial dorsal horn (SDH). This hypothesis will be tested by pursuing three specific aims: 1) Determine the extent to which a conditioning train of dorsal root A?-ES modulates high-threshold (C-fiber) evoked activity of excitatory and inhibitory neurons in the SDH in an en bloc spinal cord preparation from nave and nerve-injured mice. 2) Use in vivo imaging to determine the extent to which a conditioning train of dorsal column A?-ES attenuates peripherally evoked activity of excitatory and inhibitory neurons, in the superficial dorsal horn, in nave and nerve-injured mice. 3) Determine the role of somatostatin expressing neurons in dorsal column A?-ES mediated analgesia. The proposed approach takes advantage of state-of-the-art ex vivo and in vivo two-photon imaging coupled with optogenetic approaches to delineate the effects of A?-ES on defined neuronal populations in real time. The proposed research is significant because a detailed understanding of how A?-ES engages the dorsal horn will provide a direct biological target for enhancements to SCS therapies with a sound mechanistic basis. This work will thus have direct translational relevance, as it may help optimize spinal cord stimulation programs and improve patient outcomes. Dr. Andrei Sdrulla is a MD/PhD clinician-scientist whose career goals are to become a successful, independently funded pain researcher and a clinical leader in the field of neuromodulation. Dr. Sdrulla will work closely with his comprehensive mentorship team to develop expertise in quantitative imaging of neuronal populations, in vivo imaging, mouse models of chronic pain and optogenetic manipulation of neuronal populations in behaving animals. This training will be accomplished primarily via performing experiments under supervision from his mentors, as well as structured training consisting of didactics, face-to-face instruction and seminars. Dr. Sdrulla will be conducting his research within Oregon Health & Science University?s Department of Anesthesiology Laboratories, a uniquely collaborative environment constructed on a foundation of shared resources and core excellence, which is ideal for an early career investigator.